The overall theme of this proposal is to explore the mechanisms whereby the fetus and adult adapt to long-term, high altitude hypoxemia. In addition, we will examine several basic mechanisms involved as the fetus develops into an adult. This proposal is a broadly based, multidisciplinary program which uses biochemical, physiologic, and pharmacologic tools to explore adaptations of the cardiovascular system, the cerebral blood vessels, and the fetal hypothalamic-pituitary-adrenal axis in response to long-term hypoxemia. These studies will be conducted in fetal and adult sheep acclimatized to high altitude (12,470 feet, 3820 m) and in normoxic controls. They are based on six years of preliminary studies by our group on the responses and adaptations to high altitude hypoxia in the fetus and adult. The proposed studies move beyond descriptive changes to examine a number of hypotheses regarding biochemical mechanisms. For example, in the heart we will test hypotheses regarding the roles of calcium channels, myosin enzymes, myosin ATPase, beta receptors, receptor coupling to cAMP, and key metabolic enzymes in the responses to long-term hypoxemia. In the cerebral arteries we will test several hypotheses regarding receptors (alpha adrenergic and serotoninergic), coupling to second messengers (inositol phosphates and cAMP), the relation to intracellular calcium, vascular innervation, norepinephrine release and reuptake, et cetera, to long-term hypoxemia. In pregnant uterine arteries we will test several hypotheses regarding the mechanisms (receptors and second messengers) of acute hypoxic-induced contraction, and how these mechanisms are altered by long-term hypoxemia. Finally, we also will test several hypotheses regarding the fetal hypothalamic-pituitary-adrenal responses to long-term hypoxemia, e.g., the role of adrenal adenylate cyclase, and glucocorticoid receptors. From a scientific standpoint, these studies will augment our understanding of the mechanisms whereby the fetus and adult successfully adapt to chronic hypoxemia. In addition, they will shed light on a number of aspects of development from fetus to adult. From a clinical standpoint, these studies relate to the problems of prolonged hypoxemia and successful high altitude acclimatization. For the fetus and newborn they also relate to responses to prolonged hypoxemia as occurs in women who live at high altitude, as well as those who smoke or are exposed to environmental pollution with carbon monoxide, as well as those who are anemic, malnourished, or who have heart or lung disease or a hemoglobinopathy, or with "placental insufficiency." For the newborn infant these studies relate to problems associated with chronic hypoxia such as persistent fetal circulation, pulmonary hypertension, altered cerebrovascular function, and intracerebral hemorrhage.